US8344173B2 - Dendritic oligopeptide-grafteded cyclotriphosphazene, a process for the preparation thereof and a drug delivery system containing the same - Google Patents

Dendritic oligopeptide-grafteded cyclotriphosphazene, a process for the preparation thereof and a drug delivery system containing the same Download PDF

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US8344173B2
US8344173B2 US12/990,089 US99008909A US8344173B2 US 8344173 B2 US8344173 B2 US 8344173B2 US 99008909 A US99008909 A US 99008909A US 8344173 B2 US8344173 B2 US 8344173B2
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cyclotriphosphazene
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methoxypolyethylene
drug
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Youn Soo Sohn
Yong Joo Jun
Sung Mo Choi
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CNPHARM CO Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/22—Amides of acids of phosphorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/65812—Cyclic phosphazenes [P=N-]n, n>=3
    • C07F9/65815—Cyclic phosphazenes [P=N-]n, n>=3 n = 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/659—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having three phosphorus atoms as ring hetero atoms in the same ring

Definitions

  • the present invention relates to a dendritic oligopeptide-grafted cyclotriphosphazene capable of forming a molecular hydrogel, a process of preparing the same, and a drug delivery system including the dendritic oligopeptide-grafted cyclotriphosphazene, and more particularly, to a dendritic oligopeptide-grafted cyclotriphosphazene that is capable of forming a strong hydrogel even in a very low concentration, exhibiting a release profile of the approximate zero-order, and displaying a sustained release property of a protein drug, a method of preparing the same, and a drug carrier including the dendritic oligopeptide-grafted cyclotriphosphazene.
  • Conventional organic polymer hydrogels are formed by amphiphilic (hydrophilic and hydrophobic) polymers through chemical or physical interactions among the polymer molecules in aqueous solution, thereby forming a three-dimensional cross-linked net work, which absorbs water molecules into the void of the net work, affording an intermediate mechanical and physicochemical properties between the liquid and solid phases that does not flow.
  • Hydrogels are classified into chemical hydrogels formed by chemical crosslinking among the polymer molecules having at least two functional groups and physical hydrogels formed by random physical cross-linking through hydrogen bonding, coordinate bonding, or hydrophobic interactions.
  • a physical hydrogel is defined as a material having solid-like fluid properties and including water at equilibrium so that it is not dissolved in water (Nayak, S.; Lyon, L. A., Angew. Chem. Int. Ed. 2005, 44, 7686).
  • the molecular hydrogel that is one of the most important emerging biomaterials initially developed during the last decade was reported to have a molecular weight far less than conventional polymers (Mw>10,000) and is formed by self-assembled molecular or nano-sized fibrillar networks (SAFINs), thereby absorbing a massive amount of water molecules (Weiss, R. G.; Terech, P, Molecular Gels p 1-9, Springer: Dordrecht, The Netherlands, 2006).
  • SAFINs self-assembled molecular or nano-sized fibrillar networks
  • a gel is obtained by dissolving a small amount of a gelator in a solvent (0.1-20 w/w %) and heating or cooling the solution until it does not flow.
  • T gel the temperature at which the solution stops flowing
  • C gel a gelation concentration
  • conventional organic polymer hydrogels have a high gelation concentration in the range of 15 to 30 w/w % of aqueous solution
  • molecular hydrogels have a gelation concentration of 1 w/w % or less.
  • a gelator is dissolved in water to form a hydrogel with a secondary structure in the range of a nanosize (10 ⁇ 9 m) to a microsize (10 ⁇ 8 m).
  • the secondary structure is in the form of agglomerate having various shapes according to the molecular structure of the unimer, such as micellar, fibrous, ribbon-type, and plate-type.
  • Recently, diverse researches have been conducted into behaviors of amphiphilic polymers. As described above, agglomerated particles with various shapes have been observed (Fuhrhop, J. H.; Helfrich, W. Chem. Rev. 1993, 93, 1565). Particularly, diverse research into amphiphilic polymers has been conducted with respect to gelation by crosslinking among micelles.
  • PEG-PPG-PEG polyethylene glycol
  • ICI poloxamer
  • PEG-PPG-PEG polypropylene glycol
  • ICI poloxamer
  • PEG-PPG-PEG polypropylene glycol
  • ICI poloxamer
  • PEG-PPG-PEG polypropylene glycol
  • PAA polaxamer-polyacrylic acid
  • thermosensitive gelling i.e., thermogelling
  • a phase transition of polyethylene glycol-poly(lactic acid-glycolic acid)-polyethylene glycol (PEG-PLGA-PEG (550-2810-550)) in aqueous solution by thermogelling is closely related to its concentration and temperature.
  • the phase transition occurs in the order of transparent solution>turbid solution>translucent solution>opaque gel as the temperature increases (Jeong, B.; Bae, Y. H.; Kim, S. W.
  • thermosensitive polymers to biomedical materials mainly used as a drug delivery system, the environment, biology, and cosmetics.
  • poly(N-isopropyl acrylamide) or polyethylene oxide copolymers, hydroxy polymers, and a few polyphosphazenes were reported to exhibit thermosensitivity (K. Park Eds, Controlled Drug Delivery, 485 (1997)).
  • thermosensitive polymers are toxic and are non-degradable, they were reported to be not suitable for drug delivery.
  • the copolymer of polyethylene glycol-poly(lactic acid-glycolic acid)-polyethylene glycol has biodegradability, its degraded products are acidic enough to denature protein drugs and therefore, is not suitable for protein drug delivery.
  • amphiphilic compounds prepared by grafting equimolar hydrophilic polyethylene glycol (PEG) and hydrophobic linear oligopeptide into cyclotriphosphazene forms strong spherical micelles by self-assembly in aqueous solution (Youn Soo Sohn, et al., Angew. Chem. Int. Edit. 2006, 45, 6173-6176; WO 06/043757).
  • these cyclotriphosphazene micelles are thermosensitive but do not form a cross-linked network because the hydrophobic linear oligopeptide groups grafted to the cyclic phosphazene ring are efficiently oriented into the micelle core and not allowed for further hydrophobic interactions to cross-link with other micelles in aqueous solution.
  • these amphiphilic cyclotriphosphazenes exhibit a lower critical solution temperature (LCST) at which the cyclotriphosphazene micelles precipitate due to weakened hydrogen bonding between the hydrophilic surface of the micelles and solvent water molecules when the solution temperature of the cyclotriphosphazene micelles is increased. Therefore, the cyclotriphosphazene micelles bearing linear oligopeptides do not gelate but precipitate in aqueous solution when their solution temperature is increased.
  • LCST critical solution temperature
  • FIG. 1 is a graph illustrating viscosity of an aqueous solution of a compound according to an embodiment of the present invention of a concentration of 2 w/w % at room temperature depending on the shear rate ( ⁇ dot over (r) ⁇ );
  • FIG. 2 is a graph illustrating viscosity of an aqueous solution of a compound according to an embodiment of the present invention of a concentration of 2 w/w % with increasing temperature by 1.0° C./min;
  • FIG. 3 shows pictures of a mixture prepared by adding a compound according to an embodiment of the present invention to distilled water at room temperature, which were taken before heating, after heating to 70° C. or higher, and after cooling to room temperature;
  • FIG. 4 shows transmission electron microscopic (TEM) images of solutions of a compound according to an embodiment of the present invention dissolved in distilled water by heat-treatment with concentrations of 0.1 w/w %, 0.5 w/w %, and 1.0 w/w %, respectively;
  • FIG. 5 is a graph illustrating amounts of fluorescent albumin released from a hydrogel, measured using a fluorescence spectrometer in a phosphate buffer solution for two weeks, wherein the hydrogel is prepared using a compound according to an embodiment of the present invention with a concentration of 1 or 2 w/w % and the fluorescent albumin;
  • FIG. 6 is a graph illustrating amounts of fluorescent albumin released from a hydrogel, measured using a fluorescence spectrometer in a phosphate buffer solution for two weeks, wherein the hydrogel is prepared by adding a compound according to an embodiment of the present invention to distilled water to a concentration of 1, 2, or 4 w/w %, heating the solution to 70° C. to obtain a homogenous sol, rapidly cooling the sol to 37° C., adding a fluorescent albumin solution to the sol, and cooling the mixture to room temperature.
  • the present inventors have conducted research into a molecular hydrogel to overcome the problems of the conventional thermosensitive hydrogels described above and completed the present invention in which a dendritic tetrapeptide instead of a linear oligopeptide are introduced into cyclotriphosphazene ring along with hydrophilic polyethylene glycol.
  • the present invention provides a substance capable of forming a thermosensitive molecular hydrogel, as a protein drug carrier, having amphiphilicity (hydrophilicity/hydrophobicity), biodegradability, a sustained release property without any burst effect during the early stage of release even at a low gel concentration ( ⁇ 2%).
  • the present invention also provides a method of preparing the substance capable of forming a thermosensitive molecular hydrogel.
  • the present invention also provides a drug carrier including the thermosensitive molecular hydrogel.
  • n 7, 12, or 16
  • x 0, 1, or 2
  • R is each independently a C1-C6 alkyl or benzyl.
  • the cyclotriphosphazene of Formula 1 may be prepared using a method comprising the reaction of a cyclotriphosphazene represented by Formula 5 below including polyethylene glycol and chlorine with an ester of a dendritic tetrapeptide represented by Formula 6 below:
  • R 1 is —(CH 2 CH 2 O) n CH 3 .
  • a drug carrier comprising cyclotriphosphazene represented by Formula 1.
  • a compound represented by Formula 1 obtained by substitution with a dendritic tetrapeptide instead of the linear oligopeptide in the cyclotriphosphazene of Formula 1 disclosed in International Publication No. WO 06/043757 is capable of forming a gel having excellent mechanical strength in aqueous solution even at a low concentration of 2 w/w % or less, has biodegradability, and may be effectively used for a sustained release of a protein drug such as peptide.
  • n 7, 12, or 16
  • x 0, 1, or 2
  • R is each independently a C1-C6 alkyl or benzyl.
  • the cyclotriphosphazene of Formula 1 may be selected from the group consisting of the compounds below, but is not limited thereto:
  • monomethoxypolyethylene glycol represented by Formula 2 is reacted with sodium metal or potassium metal to prepare a metal salt of methoxy polyethylene glycol represented by Formula 3 below.
  • the ratio of the compound of Formula 2 to sodium metal or potassium metal is not limited. According to an embodiment, 1.2-1.5 equivalents of sodium metal or potassium metal may be used per 1 equivalent of the compound of Formula 2.
  • the compound of Formula 2 may be used for the reaction after moisture of the compound is removed using azotropic distillation in toluene. Any organic solvent that does not inhibit the reaction, such as tetrahydrofuran (THF), benzene, or toluene may be used for the reaction.
  • THF tetrahydrofuran
  • benzene benzene
  • toluene may be used for the reaction.
  • the reaction may be performed by refluxing in an inert atmosphere, e.g., in the presence of argon gas, for about 4 hours or more.
  • R 1 is —(CH 2 CH 2 O) n CH 3 .
  • the reaction mole ratio of the compound of Formula 3 to the compound of Formula 4 is not limited. According to an embodiment, 3.0 to 3.9 equivalents, for example, 3.0 to 3.1 equivalents of the methoxy polyethylene glycol metal salt of Formula 3 may be reacted with 1 mol (6 equivalents) of hexachlorocyclotriphosphazene (N 3 P 3 Cl 6 ) of Formula 4. Any solvent that does not inhibit the reaction, for example, a solvent selected from the group consisting of tetrahydrofuran, benzene, toluene and chloroform, and any combination thereof may be used for the reaction.
  • the solution of hexachlorocyclotriphosphazene of Formula 4 is cooled to a low temperature equal to or less than ⁇ 20° C., and the solution of the methoxy polyethylene glycol metal salt of Formula 3 is slowly added thereto.
  • an intermediate of the cyclophosphazene of Formula 5 that is a cis-nongeminal isomer may be prepared by performing the reaction at a temperature equal to or less than ⁇ 20° C. for 4 to 8 hours and at room temperature for 8 to 24 hours.
  • the said reaction at ⁇ 20° C. or lower may be performed in, for example, a dry ice-acetone bath ( ⁇ 60 to ⁇ 70° C.).
  • the mole ratio of the compound of Formula 5 to the compound of Formula 6 is not limited. According to an embodiment, 1.5 to 2.0 equivalents of the compound of Formula 6 may be reacted with each of the unsubstituted chlorine atoms in the compound of Formula 5.
  • the reaction may be performed in the presence of a base, for example, triethylamine, catalyzing nucleophilic substitution of the compound of Formula 6 with the unsubstituted chlorine atoms of the compound of Formula 5.
  • the mole ratio of the base acting as a catalyst to each of the unsubstituted chlorine atoms of the compound of Formula 5 may be a large excess, for example, 4 to 10 times.
  • Any solvent that does not inhibit the reaction for example, a solvent selected from the group consisting of tetrahydrofuran, benzene, toluene and chloroform, and any combination thereof may be used for the reaction.
  • the reaction may be performed at room temperature for about 24 hours and then at a temperature in the range of 40 to 60° C. for about 3 to 4 days with refluxing.
  • the product of the reaction may be isolated and purified.
  • the reaction solution may be centrifuged or filtered to remove precipitated by-products (Et 3 NHCl or NaCl), and the residual solution is concentrated under reduced pressure, and then, the above-mentioned organic solvent is added thereto to dissolve the concentrate.
  • the resultant solution is washed three times with water, and the organic layer is dried using a drying agent, for example, MgSO 4 .
  • the dried solution is filtered under reduced pressure, and the obtained filtrate is concentrated under reduced pressure.
  • the concentrated product is finally purified using a normal-phase chromatography, e.g., silicagel chromatography, to obtain the final compound of Formula 1.
  • the tetrapeptide compound of Formula 6 may be commercially available or may be prepared from a commercially available starting material using a method known in the literature, for example, a method disclosed by John Jones, Amino Acid and Peptide Synthesis, Oxford University Press, 32-34, (1994).
  • M is sodium or potassium
  • n, x, and R are defined above with reference to Formula 1.
  • the hydrogel has thermosensitivity, biodegradability, and compatibility with peptide and protein drugs, and exhibits a sustained release property without any burst effect in the early stage of intravenous injection.
  • the hydrogel formed from the compound of Formula 1 and water may be efficiently used for drug delivery.
  • a drug carrier including the cyclotriphosphazene of Formula 1.
  • the drug carrier may be in the form of a hydrogel including the compound of Formula 1.
  • the drug carrier may be prepared using a method that is conventionally used to prepare drug carriers using a hydrogel.
  • the hydrogel contained in the drug carrier may include 0.1 w/w % or more, for example, 0.5 to 5 w/w % of the compound of Formula 1.
  • the hydrogel is a thermosensitive gel that rapidly gelates at about 30° C. and has a viscosity of about 1.0 ⁇ 10 5 Pas at around body temperature (refer to Experimental Example 1-(2) below). Accordingly, the drug carrier including the compound of Formula 1 may gelate in the body to exhibit a sustained release of a drug contained therein.
  • the compound of Formula 1 was found to form a hydrogel very quickly in aqueous solution. While the procedure to prepare conventional organic polymer gels is complex and time-consuming (days), the hydro-gel from the compound of Formula 1 (refer to Experimental Example 1-(3) below) may be quickly prepared (within 30 minutes) by a simple procedure. For example, the compound of Formula 1 in water (1-2 w/w %) is heated with stirring to a temperature in the range of 60 to 80° C. to obtain a translucent gel, which is cooled to room temperature to obtain a clear sol (refer to Experimental Example 1-(3) below). Therefore, the drug carrier including the compound of Formula 1 may be simply prepared.
  • the drug carrier is effective for a sustained release of a protein drug and does not denature protein so as to be efficiently used for delivery of a protein drug including peptide. Furthermore, the drug carrier does not exhibit any burst effect of a drug during the early stage of the sustained release of the drug, and thus may be efficiently used for a sustained release of the drug. Furthermore, the drug carrier exhibits a zero-order release profile indicating an ideal drug release pattern.
  • the drug carrier may also delay a drug release rate by increasing the concentration of the compound of Formula 1 contained in the hydrogel (refer to Experimental Example 3 below).
  • the hydrogel prepared using the compound of Formula 1 according to the present invention may be used as various bio-materials in tissue engineering or the like in addition to the drug carrier.
  • the compound of Formula 1 may form a strong hydrogel at a very low concentration of 2 w/w % or less, while the conventional organic polymers may form a hydrogel at a very high concentration ranging from 15 to 30 w/w %.
  • the hydrogel prepared using the compound of Formula 1 exhibits biodegradability, thermosensitivity at around body temperature, biocompatibility with protein drugs, and an easy way to prepare along with a sustained release property without any burst effect in the early stage of release. Therefore, the present cyclotriphosphazene molecular hydrogel may be efficiently used as a drug carrier for a sustained release of a drug, particularly, a protein drug.
  • Sol-gel phase transition of the compound prepared in Example 2 depending on temperature was measured using a rheometer produced by Thermo-Hakke Co., Ltd. (1°, 60 mm cone).
  • Example 2 0.2 g of the compound prepared in Example 2 was added to 9.8 g of distilled water, and then was heated to 70° C. to completely dissolve the compound. Then, viscosity of the solution was measured at room temperature with changing shear rates ( ⁇ dot over (r) ⁇ ), and the results are shown in FIG. 1 .
  • Shear thinning is an effect where viscosity decreases with increasing external mechanical stimulus.
  • aqueous solution of the compound prepared in Example 2 was prepared in the same manner as in Experimental Example 1-(1) above. Then, viscosity of the aqueous solution was measured with increasing temperature from room temperature to identify a gelation temperature and the strength change of the hydrogel. The heating rate was 1.0° C./min or 0.5° C./min and the concentration of the aqueous solution was 2 w/w %. The results are shown in FIG. 2 . The temperature was increased from 5 to 75° C., but results obtained in the temperature range from 20 to 75° C. were shown. Viscosity changes in a temperature range from 26 to 39° C., i.e., body temperature range, are enlarged in a graph at the center of FIG. 2 .
  • the hydrogel had a very high maximum viscosity of 1.5 ⁇ 10 7 Pas at around 50° C. However, it was found that the viscosity is as low as about 4 Pas in the room temperature range from 20 to 30° C., but gelation starts rapidly from 30° C. and reaches a high viscosity of about 1.0 ⁇ 10 5 Pas at around body temperature according to the central graph of FIG. 2 . Thus, it was identified that the compound according to the present invention was a thermosensitive gelator, which is suitable for local delivery of drugs.
  • Example 2 0.2 g of the compound prepared in Example 2 was added to 9.8 mL of water, and the solution was stirred. Then, the phase change thereof depending on temperature was observed and photographed. First, a picture of a mixture including the compound and water before heating was taken, and a picture of the mixture heated to 80° C. or higher was taken. Finally, the heated solution was cooled to room temperature, and a picture thereof was taken.
  • the compound of Formula 2 is not soluble in water at room temperature. However, the compound is dissolved into a clear sol by heating the compound to 80° C. or higher, and a clear gel was obtained by cooling the clear sol to room temperature.
  • a gel may be quickly prepared by heating and cooling the compound according to the present invention. While the process for dissolution of conventional polymer gels is complex and time-consuming, the compound according to the present invention is advantageous in that it may quickly form a hydrogel (within about 30 minutes).
  • the hydrogel prepared using the compound according to the present invention has viscosity that is reduced with increasing shear rate and thermosensitivity by which a gelation occurs at around body temperature, and may be very quickly prepared. Accordingly, the hydrogel prepared using the compound according to the present invention may be efficiently used for drug delivery by carrying and injecting a drug at room temperature.
  • Example 2 The compound prepared in Example 2 was dissolved in water to the concentrations of 0.1 w/w %, 0.5 w/w %, and 1.0 w/w % in the same manner as in Experimental Example 1, and TEM images of the solutions were obtained.
  • FIG. 4 illustrates TEM images of the solutions.
  • the compound of Example 2 mostly exists in spherical micelles but partly starts to self-assemble into nanofibers, but at the higher concentration of 0.5 w/w %, only a fiber bundle structure was observed.
  • a more dense and cross-linked fiber bundle structure was formed at the concentration of 1 w/w %, so that a large amount (more than 100 times the weight thereof) of water molecules may be captured by the structures. Based on this result, it was identified that a molecular hydro-gel was formed by the compound according to the present invention.
  • FITC fluorescent material
  • Example 2 or 3 The compound prepared in Example 2 or 3 was dissolved in 1 ml of distilled water to a desired concentration at 70° C. to prepare a homogenous sol and the solution was rapidly cooled to 37° C.
  • a fluorescent albumin solution (2 mg/ml) (Sigma) was mixed with the solution to obtain a homogenous sol in a vial and the sol was maintained until it turned to a hydrogel. If the hydrogel is formed, 6 ml of a phosphate buffer solution (PBS) was added to the hydrogel in the vial, which was slowly shaken in a constant temperature bath at 37° C.
  • PBS phosphate buffer solution
  • FIG. 5 shows the result of the compound prepared in Example 2
  • FIG. 6 shows the result of the compound prepared in Example 3.
  • the drug release rate may be controlled by regulating the concentration of the hydrogel.

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KR101427781B1 (ko) * 2010-12-20 2014-08-13 (주)씨앤팜 양친성 고리형 포스파젠 삼합체, 양친성 고리형 포스파젠 삼합체로 미셀화한 소수성 약물제제 및 그 제조 방법
WO2015137777A1 (ko) * 2014-03-14 2015-09-17 (주)씨앤팜 신규한 양이온성 폴리포스파젠 화합물, 폴리포스파젠-약물 컨쥬게이트 화합물 및 그 제조 방법
KR102078806B1 (ko) 2014-03-14 2020-02-18 (주)씨앤팜 신규한 양이온성 폴리포스파젠 화합물, 폴리포스파젠-약물 컨쥬게이트 화합물 및 그 제조 방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010045493A (ko) 1999-11-05 2001-06-05 박호군 온도감응성을 갖는 고리형 포스파젠 삼량체 및 그의제조방법
KR20020015180A (ko) 2000-08-21 2002-02-27 박호군 온도감응성을 갖는 포스파젠삼량체-백금착물 복합체, 그의제조방법 및 그를 함유하는 항암제 조성물
WO2006043757A1 (en) 2004-10-19 2006-04-27 Ewha University - Industry Collaboration Foundation Thermosensitive and biocompatible amphiphilic cyclic phosphazene trimer and preparation method thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20010045493A (ko) 1999-11-05 2001-06-05 박호군 온도감응성을 갖는 고리형 포스파젠 삼량체 및 그의제조방법
KR20020015180A (ko) 2000-08-21 2002-02-27 박호군 온도감응성을 갖는 포스파젠삼량체-백금착물 복합체, 그의제조방법 및 그를 함유하는 항암제 조성물
WO2006043757A1 (en) 2004-10-19 2006-04-27 Ewha University - Industry Collaboration Foundation Thermosensitive and biocompatible amphiphilic cyclic phosphazene trimer and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
International Search Report for PCT/KR2009/002190, mailed Dec. 17, 2009.
Yong Joo Jun et al, Bioorganic Medicinal Chemistry Letters, 17, 2007, 2975-2978. *

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